Inhalable aerosolized drugs for inhalation are generally considered as conceivable alternatives to injections or other types of drug-delivery systems, such as intravenous delivery, subcutaneous or intramuscular injections. For example, insulin is desirable to deliver by inhalation of an aerosolized form to improve patient compliance. It is, however, a general problem with inhalable aerosols that the delivered dose is inaccurate in comparison to injections and the correct amount required for delivery frequently is not properly metered for delivery. Both for systemic drug delivery and for screening of drugs with aerosol using pulmonary models, a low level of accuracy is a drawback for appropriate use both for a safe therapy or a resourceful screening model.
For the most part in the clinic, it is desirable to deliver a predetermined dose of drug with as short exposure time as possible—preferably a single-breath inhalation maneuver dispensing a well-controlled bolus of aerosolized drug at a high concentration to the respiratory tract. It would therefore be equally desirable to mimic this exposure strategy also in the early drug development process in order to collect as relevant data as possible. However, because of technical limitations in most aerosol generator technologies and delivery systems, this has rarely been achieved. Most available generator technologies have continuous outputs consuming large amounts of substance. It is the intent of the current invention to overcome this limitation and enable bolus type exposures to respirable aerosols also in early drug development.
U.S. Pat. No. 6,003,512 describes a dust gun aerosol generator and methods of aerosolizing and dispensing powders. This equipment provides inhalable aerosols with highly repeatable properties from small amounts of powders. The high deagglomeration power of the equipment provides for that diluents and excipients can be avoided and that a highly repeatable, suitably concentrated aerosol dose with homogenous particle size is generated even from small amounts of cohesive powders. Accordingly the dust gun aerosol generator has showed to be a useful tool to combine with an isolated, ventilated and perfused lung of rodents (IPL), as is disclosed in P Gerde et al. Inhalation Toxicology, 2004, 16, 45-52 wherein the pulmonary deposition of diesel soot was studied. U.S. Pat. No. 5,887,586 (Dahlbäck et al.) discloses a method and a system for measuring a dose inhaled by an animal from an aerosolized drug. The system comprises means for more accurately measuring the inhaled dose. It does however, suffer from a drawback in that the distance between the aerosol generator and the animal becomes rather long, resulting in a high dead space leading to significant losses of aerosolized drug in the system and in that a relatively high amount of drug never reaches the lungs of the animal. Loss of drug to deposition in equipment is highly unwanted, particularly in the early stage of drug candidate screening due to economic reasons. U.S. Pat. No. 6,269,810 describes a pulmonary dosing system and methods of its operation strictly for therapeutic purposes. The system depends only on filters for calibration, which is insufficient for an accurate estimation of the deposited to dose with respect to aerosol losses from aerosol generator to the exposure target necessary when for example evaluating the performance of drug candidates.
During inhalation exposures with drug substance candidates, deposition of a studied substance in the target region of the lungs is a desired process that is always accompanied by unwanted losses of study material through deposition in delivery equipment and in non-target regions of the respiratory tract. Early in the development process of drugs intended for inhalation delivery, substance loss is a critical factor preventing often decisive early tests via inhalation. Two major mechanisms lead to wall deposition of particles when an aerosol is flowing through a duct: aerodynamic losses and electrostatic losses. Aerodynamic losses are contributed by diffusion, sedimentation, impaction, and interception of particles and are influenced primarily by the mass median aerodynamic diameter (MMAD) of the studied aerosol and by the fluid dynamics of the duct system under study. Aerodynamic losses can be reasonably well predicted with theoretical models. Electrostatic losses are superimposed on the aerodynamic losses, and depend strongly on material properties of the studied powder and the walls of the duct system. Electrostatic losses are more erratic and difficult to predict, and can be the dominating deposition mechanism of a studied aerosol. This unpredictable behaviour of powder aerosols leads to substance losses not only to vessel walls of aerosol generator equipment, exposure systems, and to non-target regions of the respiratory tract, but also during the adjustment of exposure parameters needed to attain target exposures in study subjects. It is the intent of the current invention to address both these problems;
A specific problem with bolus type inhalation exposures is to control both the aerosol concentration and the duration of the aerosol presence in the inhaled gas. In the ideal situation, the aerosol is present at a predetermined concentration in the inhaled gas between time on and time off, determined by the breathing pattern of the exposure subject. The aerosol concentration should represent a square wave without dispersion or tailing in the end. However, this is difficult to accomplish and a typical concentration curve for an aerosol bolus is uneven and contains a longer tail of gradually decreasing concentration. One fundamental mechanism affecting aerosol boluses of dense aerosols is the cloud settling phenomenon (NA Fuchs, The Mechanics of Aerosols, Pergamon Press, Oxford UK, 1964). Dense aerosols with an average density that is only slightly higher than the surrounding air tend to move in separated clouds where the cloud moves faster than the individual particles relative to their surrounding gas matrix (see W C Hinds et al., Aerosol Science and Technology, Vol. 36, pp. 1128-1138, 2002). Cloud settling can be a major factor contributing to an increased dispersion of an aerosol bolus, particularly of the terminating end of an aerosol exposure. Such dispersion can prevent substantial parts of an intended aerosol dose from reaching the target area of the respiratory tract or usually depositing instead in the exposure equipment or arriving in the target area outside the predetermined time window.
Intermittent, burst-type of aerosol generators such as the aforementioned dust gun or the Exubera® (Pfizer Inc.) eject a plume of aerosol into a more or less stagnant medium. The kinetic energy of the deagglomerating burst quickly dissipates, and a characteristic plume is formed. Subsequently, the plume will be affected by diffusional, convective, and gravitational forces that will disperse and dilute the aerosol of the plume. For inhalation exposures it is most often a desire to convert the burst plume into an aerosol bolus to be inhaled by an exposure subject in one or several breaths. The aerosol bolus should present a step increase in aerosol concentration from zero to a constant level and remain level until the bolus ends with a step decrease to zero from the average concentration. Ideally the bolus average concentration should be the amount of substance loaded and aerosolized divided by the bolus volume
Thus, a need exists for accurately and predictably delivering a predetermined dose of aerosolized drugs with minimized substance losses in the equipment and to reach target dose without any range-finding exposures with tissues or animals. There is also a need for a system that allows for accurate testing of aersoslizable drug candidates in very early stage when only small amounts of substances are available. For these purposes, an exposure system has been assembled by connecting the aerosol generator through a manifold arrangement with an isolated perfused lung or with the respiratory tract of intact animals. It is apparent that the mentioned exposure system including the dust gun aerosol generator can be efficiently employed when screening and evaluating new drug candidates for local action in the lungs or for systemic uptake through pulmonary administration. Especially, the dust gun system can be part of an arrangement and a methodology, which greatly reduces quantities and pre-processing of synthesized drugs, simplifies the screening process, while reducing the employment of biological material including test animals. The invention as described in the following sections is adapted to meet such requirements.